mTOR- and HIF-1 alpha-mediated aerobic glycolysis as metabolic basis for trained immunity

作者：Cheng, Shih-Chin; Quintin, Jessica; Cramer, Robert A.; Shepardson, Kelly M.; Saeed, Sadia; Kumar, Vinod; Giamarellos-Bourboulis, Evangelos J.; Martens, Joost H. A.; Rao, Nagesha Appukudige; Aghajanirefah, Ali; Manjeri, Ganesh R.; Li, Yang; Ifrim, Daniela C.; Arts, Rob J. W.; van der Meer, Brian M. J. W.; Deen, Peter M. T.; Logie, Colin; O'Neill, Luke A.; Willems, Peter; van de Veerdonk, Frank L.; van der Meer, Jos W. M.; Ng, Aylwin; Joosten, Leo A. B.; Wijmenga, Cisca; Stunnenberg, Hendrik G.

来源：Science, 2014, 345(6204): 1579-+.

DOI：10.1126/science.1250684

• INNATE IMMUNITY
• BETA-GLUCAN
• CELLS
• MACROPHAGES
• ACTIVATION
• INFECTION
• INFLAMMATION
• REINFECTION
• EXPRESSION
• PROTECTION

Epigenetic reprogramming of myeloid cells, also known as trained immunity, confers nonspecific protection from secondary infections. Using histone modification profiles of human monocytes trained with the Candida albicans cell wall constituent beta-glucan, together with a genome-wide transcriptome, we identified the induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD+) to its reduced form (NADH), reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1-Akt-HIF-1 alpha (hypoxia-inducible factor-1 alpha) pathway. Inhibition of Akt, mTOR, or HIF-1 alpha blocked monocyte induction of trained immunity, whereas the adenosine monophosphate-activated protein kinase activator metformin inhibited the innate immune response to fungal infection. Mice with a myeloid cell-specific defect in HIF-1 alpha were unable to mount trained immunity against bacterial sepsis. Our results indicate that induction of aerobic glycolysis through an Akt-mTOR-HIF-1 alpha pathway represents the metabolic basis of trained immunity.

• 出版日期2014-9-26